Control of GVHD by milatuzumab in hu-SCID mice Dendritic cells (DCs) are the primary initiator of graft-versus-host disease (GVHD), a major and life- threatening complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). Depletion of DCs has been demonstrated to be an effective approach for control of GVHD. We recently found that milatuzumab, a humanized anti-CD74 monoclonal antibody, can efficiently deplete myeloid DCs from human peripheral blood mononuclear cells, and potently suppress the proliferation of alloreactive T cells without impairing CMV-specific CD8+ T cells in allogeneic mixed leukocyte cultures, suggesting that milatuzumab may be developed as a novel mAb for prophylactic and/or therapeutic control of GVHD. In this proposed study, we will evaluate the efficacy of this novel mAb for its prophylactic efficacy against GVHD in a human-PBL-SCID mouse model. We will also investigate whether milatuzumab, while controlling GVHD, has any detrimental effect on the "third-party" immunity in this model, including anti-viral and graft-versus-leukemic functions, which will provide key safety information for clinical use of this mAb in patients undergoing allo-hematopoietic stem cell transplant. We believe that this STTR project, through the collaboration between Immunomedics, Inc., and the Center for Molecular Medicine and Immunology, could lead to the development of a novel class of monoclonal antibodies for better control of GVHD through depletion of CD74-expressing myeloid DCs. PUBLIC HEALTH RELEVANCE: Control of GVHD by milatuzumab in hu-SCID mice Graft-versus-host disease (GVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. Milatuzumab, a humanized anti-CD74 monoclonal antibody, can efficiently deplete dendritic cells from human peripheral mononuclear cells, suggesting its potential to prevent and/or treat GVHD. We will evaluate the preventive efficacy of milatuzumab on GVHD in a "humanized" mouse model, and while controlling GVHD, if it has any harmful effect on the host immunity against pathogens and leukemia, including anti-viral and graft-versus-leukemic functions. This preclinical study could provide valuable information to justify future clinical investigations.